RESUMO
Cognitive impairment (CI) and memory deficit are prevalent manifestations of multiple sclerosis (MS). This study explores the therapeutic potential of arbutin on memory deficits using a rat hippocampal demyelination model induced by lysophosphatidylcholine (LPC). Demyelination was induced by bilateral injection of 1% LPC into the CA1 area of the hippocampus, and the treated group received daily arbutin injections (50â¯mg/kg, i.p) for two weeks. Arbutin significantly improved memory impairment 14 days post-demyelination as assessed by Morris water maze test. Histological and immunohistochemical analyses demonstrated that arbutin reduced demyelination suppressed pro-inflammatory markers (IL-1ß, TNF-α) and increased anti-inflammatory cytokine IL-10. Arbutin also diminished astrocyte activation, decreased iNOS, enhanced anti-oxidative factors (Nrf2, HO-1), and exhibited neuroprotective effects by elevating myelin markers (MBP) and brain derived neurotrophic factor (BDNF). These findings propose arbutin as a potential therapeutic candidate for multiple sclerosis-associated memory deficits, warranting further clinical exploration.
Assuntos
Anti-Inflamatórios , Arbutina , Doenças Desmielinizantes , Modelos Animais de Doenças , Lisofosfatidilcolinas , Transtornos da Memória , Fármacos Neuroprotetores , Animais , Lisofosfatidilcolinas/farmacologia , Ratos , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Masculino , Arbutina/farmacologia , Arbutina/administração & dosagem , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/induzido quimicamente , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Ratos Sprague-DawleyRESUMO
BACKGROUND: Fractalkine (CX3CL1) is a key chemokine, affects neuronal cell communication and involves in Alzheimer's disease pathogenesis. Microvesicles (MVs) participate in neuronal cells' cross-talk in physiological and pathological states. Microvesicles released in cerebrospinal fluid (CSF) may provide a valuable footprint of brain changes. Little information is available regarding the release of fractalkine-positive MVs (CX3CL1+ -MVs) in the nervous system. METHODS: We induced cognitive impairment by bilateral injection of amyloid-beta (Aß) into the cerebral ventricles. We analyzed the CSF by flow cytometry in two experiments (trained and untrained) to elucidate the presence of CX3CL1+ -MVs. The hippocampal TNF-α as an inflammatory factor was assessed by immunohistochemistry. RESULTS: The Aß induced spatial memory impairment after two weeks, verified by a decrease in the escape latency in Morris water maze test. It caused an increase in the anxiety-like behaviors demonstrated by a decrease in entries into the open arms of elevated plus maze test. The Aß increased the percent of the positive area for TNF-α staining. Histological evaluation of the hippocampus confirmed the tissue injuries. The CSF levels of CX3CL1+ -MVs, increased 2 and 7 days after Aß injection. The Aß increased the TNF-α staining and provided an inflammatory context to facilitate the MVs release. The rise of CX3CL1+ -MVs was transient and subsided after two weeks. Both trained and untrained experiments showed a similar rise pattern of CX3CL1+ -MVs. CONCLUSION: Increase of fractalkine-positive microvesicles preceded the cognitive impairment, more studies are required to approve the CX3CL1+ -MVs as a potential biomarker in the early diagnosis of Alzheimer's disease.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Doença de Alzheimer/patologia , Biomarcadores/líquido cefalorraquidiano , Quimiocina CX3CL1 , Humanos , Transtornos da Memória , Memória Espacial , Fator de Necrose Tumoral alfaRESUMO
Deficits in the translation between egocentric-allocentric strategies may become another diagnostic mark for neurodegenerative disorders, especially Alzheimer's disease. Regarding the specific regional distribution of serotonin-1A receptor in brain areas mediating allocentric (externally-centered) spatial navigation to the escape location, here we studied the effects of median raphe nucleus serotonin-1A autoreceptors stimulation, [8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT); 4 µg/0.5 µl saline], of a selective cholinergic denervation by intracerebroventricular administration of the 192IgG saporin (1µl/each ventricle), on male Wistar rats search strategies in a Morris maze during acquisition, and before probe sessions. Despite some evidence of spatial hippocampal dependent knowledge to those PBS/Saline animals, their performance dropped to chance levels on probe trial. Therefore, we considered two probabilities and first analyzed the ability of the rats to make better use of one or more strategies. We showed statistically significant increases in the distances associated with egocentric (body-centered) non-spatial strategies, random searching in particular, in 192IgG/8OH rats, which led to their improved performance. Second, considering to what extent a shift in search strategy use improves performance indicated that 8-OH-DPAT alone did not affect learning since it appeared the related performance was impaired over days. However, the strategy choices made by 192IgG/8OH rats increased performance by more than 12% compared to 192IgG/Saline rats, an effect reversed with pre-treatment by serotonin-1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide (WAY 100635). The results strongly suggest the potential role of serotonergic system, via the serotonin-1A receptors, in spatial navigation. We argue that the receptors are of interest as therapeutic targets that can be used against age-related cognitive decline.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Anticorpos Monoclonais/farmacologia , Encéfalo , Piperazinas/farmacologia , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Saporinas/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Navegação Espacial , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Colinérgicos/farmacologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Infusões Intraventriculares , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Navegação Espacial/efeitos dos fármacos , Navegação Espacial/fisiologiaRESUMO
Background: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare inborn immune error characterized by a triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP), and adrenal insufficiency (ADI).Methods: Literature search was conducted in PubMed, Web of Science, and Scopus databases using related keywords, and included studies were systematically evaluated.Results: We reviewed 938 APECED patients and the classic triad of APECED was detected in 57.3% (460 of 803) of patients. CMC (82.5%) was reported as the earliest, HP (84.2%) as the most prevalent, and ADI (72.2%) as the latest presentation within the classic triad. A broad spectrum of non-triad involvements has also been reported; mainly included ectodermal dystrophy (64.5%), infections (58.7%), gastrointestinal disorders (52.0%), gonadal failure (42.0%), neurologic involvements (36.4%), and ocular manifestations (34.3%). A significant positive correlation was detected between certain tissue-specific autoantibodies and particular manifestations including ADI and HP. Neutralizing autoantibodies were detected in at least 60.0% of patients. Nonsense and/or frameshift insertion-deletion mutations were detected in 73.8% of patients with CMC, 70.9% of patients with HP, and 74.6% of patients with primary ADI.Conclusion: Besides penetrance diversity, our review revealed a diverse affected ethnicity (mainly from Italy followed by Finland and Ireland). APECED can initially present in adolescence as 5.2% of the patients were older than 18 years at the disease onset. According to the variety of clinical conditions, which in the majority of patients appear gradually over time, clinical management deserves a separate analysis.
Assuntos
Poliendocrinopatias Autoimunes , Adolescente , Autoanticorpos , Mutação da Fase de Leitura , Humanos , Mutação , Poliendocrinopatias Autoimunes/genética , Fatores de TranscriçãoRESUMO
BACKGROUND: Methamphetamine (Meth), a neurotoxin, induces inflammation, oxidative stress, and triggers endothelial dysfunction and cardiovascular disease which is the second cause of death among individuals with Meth-use disorder. Oxidative stress and inflammation trigger the microparticle (MP) release. These are extracellular vesicles extracted from cell surface and identified in biological fluids. MP levels alter during pathological conditions, suggesting its potential biomarker role. In this respect, we designed the present experiment to investigate the effects of Meth on the plasma level of the endothelial-derived microparticle (EMP). METHODS: Animals received Meth (4â¯mg/kg i.p.) for 1, 7 and 14â¯days and then, the plasma level of EMPs was evaluated, using cell surface markers, including AnnexinV, CD144, CD31, CD41a antigens with the flow cytometry method. The biochemical indices and locomotor activity were also assessed in a rat model. RESULTS: Meth increased locomotor activity (Meth-1, 277.12⯱â¯20.17; Meth-7, 262.25⯱â¯11.95; Meth-14, 265.75⯱â¯14.75), inflammatory and oxidative indices as evidenced by rising of the C-reactive protein (Meth-7, 39.4⯱â¯1.24; Meth-14, 38.58⯱â¯2.19, vs 8.65⯱â¯0.45, mg/L) and malondialdehyde (Meth-7, 9.74⯱â¯1.38; Meth-14, 14.6⯱â¯1.45, vs 4.43⯱â¯0.32 nmol/L) plasma levels. We also found that Meth triggered endothelial injury, as demonstrated by elevated levels of EMP (Meth-7, 4.77⯱â¯0.22; Meth-14, 5.91⯱â¯0.34, % total events/mL) compared with control group. CONCLUSION: Our data showed that Meth exposure stimulates inflammatory and oxidative pathways and facilitates the EMPs shedding. Measuring the level of EMPs might be applied as a potential diagnostic index to monitor the endothelial dysfunction in substance-use disorders.
Assuntos
Micropartículas Derivadas de Células/efeitos dos fármacos , Micropartículas Derivadas de Células/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Metanfetamina/toxicidade , Animais , Biomarcadores/sangue , Citometria de Fluxo/métodos , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Metanfetamina/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos WistarRESUMO
Cerebrovascular lesions, a potent stimulus for endothelial cell activation, trigger cognitive and degenerative changes and contribute to pathology of Alzheimer's disease (AD). Circulating microparticles (MPs) are actively involved in the pathogenesis of AD and cerebrovascular diseases, which share common vascular risk factors. We examined the plasma changes of endothelial MPs (EMPs) and platelet MPs (PMPs) in AD patients with vascular risk factors. The plasma Annexin V+ CD 41a- CD144+ EMPs and Annexin V+ CD41a+ CD144- PMPs of 37 patients with AD, with or without vascular risk factors (hypertension, diabetes, dyslipidemia, stroke, coronary artery disease, and smoking), and 10 age-matched controls were quantified by flow cytometry. Pearson correlation analysis used to evaluate the linear relationship between variables. Significantly higher plasma levels of EMPs were observed in AD patients with vascular risk factors as compared to the patients without vascular risk factors [Mean Difference (MD): 2587.80, 95% confidence interval (CI) 770.30-4404.80], and control subjects (MD: 4990.60, 95% CI, 3054.40-6926.79). Significant correlations were found between circulating EMPs, total MPs, and PMPs. There were no significant correlations between plasma levels of EMPs/ PMPs, and cognitive decline indices. Circulating EMP levels are influenced by AD disease status, and plasma levels of MPs and PMPs are associated with vascular risk factors in patients with AD. EMP phenotyping, as cellular biomarkers of vascular injury/dysfunction, and their effects on cerebral perfusion, and cognitive decline should be further investigated. Graphical abstract Vascular endothelial cell activation results in release of endothelial-derived microparticles (EMPs), which contributing to vascular dysfunction and cognitive decline.
Assuntos
Doença de Alzheimer/patologia , Micropartículas Derivadas de Células/metabolismo , Micropartículas Derivadas de Células/patologia , Células Endoteliais/metabolismo , Idoso , Idoso de 80 Anos ou mais , Caderinas/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Piperine has been shown to have antioxidant activity and a cognitive-enhancing effect following long-term oral administration. In a comparative study of memantine, the current investigation threw light on the cognitive benefits of piperine. Lipid peroxidation and the ferric reducing antioxidant power (FRAP) of cerebrospinal fluid (CSF) and hippocampus in streptozotocin (STZ)-induced experimental dementia of the Alzheimer's type was measured. After reaching a criterion in a memory test, STZ-induced rats received piperine [2.5, 5, and 10mg/kg, intraperitoneally (i.p.)], vehicle, and memantine (10mg/kg, i.p.) for two weeks after the first STZ administration, or two weeks before and one week after, as a preventive approach. After the behavioral studies, samples were taken for biochemical and histological assays. An appropriate concentration of piperine (2.5mg/kg), on a daily basis, effectively increased the number of correct (non-repeated) arm entries and repressed reentry to a previously visited arm, in terms of reference errors as well as memantine (10mg/kg, i.p.), irrespective of the dose administered. The cognitive-enhancing effect induced by piperine at a relevant dose was simultaneous with CSF and hippocampal malonaldehyde decrement, and the redox balance was established to some extent by maintaining the FRAP levels of CSF near to those of the control. Similarly, the neuroprotective properties of piperine are in accordance with histopathological outcomes, which have shown an increased number of live cresyl violet (CV)-positive neurons in a dentate gyrus (DG) subregion. Therefore, the effects of piperine on the redox balance of CSF and hippocampal neurons may certainly contribute to the cognitive-enhancing activity of the drug.
Assuntos
Alcaloides/uso terapêutico , Benzodioxóis/uso terapêutico , Transtornos Cognitivos , Inibidores das Enzimas do Citocromo P-450/uso terapêutico , Hipocampo/metabolismo , Malondialdeído/líquido cefalorraquidiano , Memantina/líquido cefalorraquidiano , Piperidinas/uso terapêutico , Alcamidas Poli-Insaturadas/uso terapêutico , Análise de Variância , Animais , Antibióticos Antineoplásicos/toxicidade , Aprendizagem da Esquiva/efeitos dos fármacos , Transtornos Cognitivos/líquido cefalorraquidiano , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/patologia , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Wistar , Estreptozocina/toxicidadeRESUMO
The DHCR24 (24-dehydrocholesterol reductase) gene codes a multifunctional protein which consists of enzymatic, antioxidant, and anti-apoptotic activities. It exists in almost all neurons and protects the neural cells against amyloid ß toxicity. Several studies have shown the down regulation of DHCR24 in Alzheimer's disease. We examined the time profile of DHCR24-mRNA alteration in an animal model of streptozotocin (STZ)-induced cognitive impairment. The DHCR24 mRNA levels of hippocampus and cognitive impairment were evaluated at 7, 14, and 21 days after intracerebroventricular (ICV)-STZ/Saline administration. DHCR24 expression was down regulated at 14 and 21 days after ICV-STZ administration. The decrease in expression of DHCR24 preceded the onset of the cognitive impairment. These results suggest the potential relation between DHCR24 expression and cognitive impairment.
Assuntos
Transtornos Cognitivos/metabolismo , Hipocampo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Animais , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/patologia , Regulação para Baixo , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto , Proteínas do Tecido Nervoso/genética , Neurônios/patologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , EstreptozocinaRESUMO
Alzheimer's disease (AD), can be described as a vascular disorder, is characterized by endothelial and platelet activation. One feature of activated cells is loss of lipid asymmetry, and membrane blebbing which cause microparticle (MP) formation. MPs increased under many pathological states and little information is available relating to their changes in AD. The purpose of this work was to characterize the time course of the endothelial-derived microparticles (EMPs) and platelet-derived microparticles (PMPs) alteration after intracerebroventricular (ICV) injection of streptozotocin (STZ). Rats were injected bilaterally with ICV-STZ/Saline, cerebrospinal fluid (CSF) and plasma EMPs (Annexin V(+) CD61(-)CD144(+)) and PMPs (Annexin V(+) CD61(+)CD144(-)) were analyzed with flow cytometry at 2 h, 4 h, 24 h, 4 days, 7 days, 14 days and 21 days after ICV-STZ/Saline administration. Cognitive impairment, malondialdehyde (MDA) level of hippocampus, plasma serotonin, and serum S100B were also assessed. We showed the elevation of CSF and plasma level of EMPs and PMPs, which may represent a proinflammatory and prothrombotic status. These alterations were simultaneous with the hippocampal MDA rise, plasma serotonin increment, and S100B decrement, 7 days after ICV-STZ administration and precede the onset of cognitive impairment. Understanding the profile of MP changes in CSF or plasma as biomarkers from tissues undergoing activation or damage, may be helpful in prediction or early diagnosis of AD.